Healthy neuron axons in the brain are wrapped by myelin sheath, which is formed by fatty layers of myelin. The myelin sheath is critical for the communication of bioelectric signal among different regions of the brain. Myelin can increase the speed at which signals travel between brain cells by up to 100-fold compared to axons lacking myelin. Destruction of the myelin sheath, a.k.a. demyelination, can impair brain functions and is considered a primary pathology of several white matter diseases, such as multiple sclerosis (MS) and leukoencephalopathies. Impaired myelination is also considered as an important pathology in Alzheimer's disease and several psychiatric disorders, such as schizophrenia and autism.
Multiple Sclerosis (MS) is an inflammatory disease of the central nervous system (CNS), which includes the brain and the spinal cord. Demyelination of white matter (WM) in the CNS is considered a major pathological factor for MS. MS is believed to be an autoimmune disease in which the immune system attacks a component of myelin in the central nerve system. T cells, which are one type of white blood cells in the immune system, become sensitized to myelin and cross the blood-brain barrier into the central nervous system, causing damages to myelin and axons. Demyelination can occur much earlier than the time when MS can be diagnosed using current diagnostic standards. One study found only 2% myelin content in an MS lesion compared to 10% in normal-appearing WM. Low myelin content in MS lesions has also been verified by post-mortem studies. Demyelination has also been suggested to be the dominant feature of normal-appearing WM pathology in MS. The identification of demyelination can be used as a significant predictor of the prognoses of the clinically isolated syndrome and for earlier diagnosis and treatment of MS. Quantitative measurement of remyelination would allow physicians to assess the effectiveness of treatment.
Demyelination has also been found to be related to Alzheimer's disease. A recent study suggests that demyelination, along with axonal degeneration, may be the cause for the observed increase of apparent diffusion coefficients in hippocampus and corpus callosum of patients with mild cognitive impairment. In addition, recent diffusion tensor imaging (DTI) studies found reduced fractional anisotropy in the frontal and temporal WM in mild cognitive impairment and early Alzheimer's disease. A post-mortem neuropathological study has confirmed the reduction of myelin density in Alzheimer's disease. Substantial recent evidence also suggests that disregulation of myelination is associated with schizophrenia, autistic disorder, and development disorders. In fact, one study found that the left corpus callosum in genu had 36% lower myelin content in schizophrenia patients than in healthy volunteers.
MRI has been used to detect pathology including focal and diffuse hyperintense lesions, hemorrhage, and atrophy with greater sensitivity than computed tomography. Although MRI provides excellent anatomic details, interpretation of MRI results is influenced by the experience and skill of the interpreter. A quantitative characterization of the raw data can provide a more objective reflection of the physiological status of the subject. For instance, MRI can provide quantitative data regarding the relaxation properties of water in different chemical environments induced by inflammatory diseases of the brain. The spin-lattice (T1) and spin-spin relaxation times (T2) provide information regarding the total water in brain, the compartmentalization of brain water, and the degree of association between this water and macromolecules such as myelin and protein.
Several MRI techniques have been used to detect signal changes that may be associated with demyelination in MS. The Magnetization Transfer (MT) technique has been used to measure the fraction of protons in a semisolid pool, fb, which contains protons bound to macromolecules (such as myelin), relative to the protons in a free pool (mostly in water) using the various models. Studies have shown a reduction of fb in MS lesions and normal appearing white matter (NAWM) compared to control WM. Although fb can be used as an indicator of myelin integrity, it is not a direct measurement of myelin water fraction (MWF), because myelin is not the only macromolecule presented in WM or gray matter (GM). Moreover, correlations between the semisolid proton fraction and myelin and axonal density have not been well established.
Another approach is called diffusion-weighted imaging (DWI), which attempts to characterize tissues based on the random translational motion of water protons. In biological tissue, normal hindrance of the mobility of water protons occurs from structural elements such as cell membranes and subcellular organelles. Thus, the mobility of water protons differs from organ to organ. Pathologic processes tend to alter the magnitude of this organization by either a destruction or reduplication of membranous elements or by a change in cellularity, e.g., scarring, inflammatory, or neoplastic infiltration. Shifts in the number of water protons between tissue compartments may be caused by changes in permeability, osmolarity, active transportation or other alterations. All these alterations may have an impact on proton mobility or diffusivity. Because these movements may occur in all directions, they are termed isotropic diffusion.
In normal tissues, a directional portion of diffusion, called diffusion anisotropy, may exist which is associated with the presence of tubular structures such as neuronal fibers. This anisotropy derives from the fact that water molecules move more readily along a fiber than perpendicular to the fiber. Myelinated fibers, such as those in the brain, exert strong anisotropic effects due to their multiple circular lipid bilayers, and this phenomenon increases with the density of fibers running in parallel. Therefore, a decrease in diffusion anisotropy may signal structural disintegration of the brain. Specifically, this indicator may be used not only to detect damage to major neuronal pathways focally, but also to detect damage remotely for lesions caused by degeneration.
Accurate determination of the complete diffusion information requires DWI with at least six diffusion-encoding gradient directions followed by a series of calculations called diffusion tensor imaging (DTI). DTI has recently been used to assess the integrity of myelin sheaths and axons by measuring the fractional anisotropy (FA) of diffusion tensor, which indicates the degree of cylindrical confinement of the water in intra- and extra-axonal spaces. WM tractography with DTI which has been used to evaluate the axons passing through local MS lesions, may potentially provide a better understanding of damage to myelin sheaths and axons and predict the development of disability. Recent animal studies using DTI also provide strong evidence that the increase in diffusivity in a direction perpendicular to the axons indicates the break down of myelination, while the decrease in diffusivity in a direction parallel to the axons indicates the presence of axonal damage.
While DTI may provide significant insights to the pathology of MS and may potentially differentiate axonal damage from demyelination, the complexity of axonal tracks, such as fiber-crossing, may introduce substantial errors in DTI-based measurements, or even render such measurements less meaningful in many regions of the brain. In addition, diffusion anisotropy serves as an indirect indicator of the maturity and integrity of WM, rather than a direct physiological measurement.
By contrast, quantitative mapping of MWF is a direct measurement of the amount of myelin in WM. It may provide a direct indicator of the integrity of the myelin sheath and may offer valuable insights into the pathology of focal lesions and NAWM. A successful technique for quantitative mapping of the MWF was developed by MacKay et al. This technique uses a 32-echo Carr-Purcell-Meiboom-Gill (CPMG) technique to acquire the MRI signal of white matter. A nonnegative least squares (NNLS) algorithm is then used to estimate the MWF from the compartment with a short T2 decay constant. This technique demonstrates the merit of quantitative measurement of MWF in studying the pathology of MS. However, at least three major issues are associated with this technique.
First, it is difficult to shorten the first echo time (TEI) and echo spacing (ES) with the CPMG technique. With the TE1 and ES values that are typically used, the myelin water signal with T2 at 15 ms is only effectively detected in the first 2-3 measurements (i.e., first 2-3 echoes), leading to compromised accuracy in estimating the MWF using multi-exponential fitting. For example, the myelin signal with T2 at 15 ms is reduced to 51% at the 1st echo, 26% at the 2nd echo, and 13.5% at the 3rd echo with TE1 at 10 ms and ES at 10 ms. In this technique, the T2 decay is acquired at each pixel using a train of non-selective inversion pulses. The TE1 of the echo train is 10 ms and the ES is 10 ms, allowing the acquisition of only a few time points during the decay of the myelin water signal. An average of four scans is usually needed (at 1.5 T) with a total scan time of 25-28 minutes to increase the signal-to-noise ratio (“SNR”) for data analysis. In addition, with the relatively long TE1 and ES, the detected myelin water signal is more heavily weighted by the myelin water with a longer T2 (15-40 ms).
Secondly, the CPMG technique acquires signals from one slice during a 25-28 minute scan, making it difficult to analyze multiple lesions that cannot be evaluated by a single slice. While this technique has proven to be effective in detecting the demyelination in MS lesions and normal appearing white matter, the lack of volume coverage, as well as the long image acquisition time, has severely limited the use of this technique in the research and clinical diagnosis of MS.
Lastly, the accuracy of the MWF measurements may be compromised because the T2's of myelin water are not well defined using the NNLS algorithm. For the T2 range of myelin water (10 ms<T2<50 ms) used in the NNLS algorithm, a substantial “signal leakage” between myelin water and myelinated axon water (T2˜40 ms; T2=29.7 ms (Bovine optical nerve samples, 7 Tesla)) may occur due to possible overlap of their T2 ranges.
In summary, the current MRI technique for myelin mapping is not adequate for routine clinical exams and neurological studies due to its long imaging time and reduced volume coverage. A direct and quantitative mapping of myelin content which overcomes these inadequacies could be used in (1) early characterization and diagnosis of MS; (2) differentiation of demyelination and axonal damages in MS lesions; (3) exclusion of inflammation-induced hyperintensity foci in T2 MRI from demyelination pathology; (4) assessment of the myelination in patients with psychiatric disorders; (5) longitudinal studies of WM maturation in children and adolescents; and (6) longitudinal studies of neuro-degeneration in elders, such as Alzheimer's disease.
Therefore, there remains a need for a quantitative method for multi-slice mapping of myelin water fraction that may be completed within a short period of time. There is a further need for a method to process data by reducing the “signal leakage” between myelin water and myelinated axon water.